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Beta-1,4-galactosyltransferase 1 (B4GALT1) is a member of the beta-1,4-galactosyltransferase gene family which encode type II membrane-bound glycoproteins that play a role in the biosynthesis of different glycoconjugates and saccharide structures. The enzyme encoded by B4GALT1 plays a critical role in the processing of N-linked oligosaccharide moieties in glycoproteins, and protein-linked sugar chains often modulate the biological functions of the glycoprotein. Thus, an impaired B4GALT1 activity has potential to alter the structure of all glycoproteins containing N-linked oligosaccharides. The long form of the B4GALT1 enzyme is localized in the trans-Golgi, where it transfers galactosyl residues to N-acetylglucosamine residues during the course of biosynthetic processing of high-mannose to complex-type N-linked oligosaccharides. Because addition of galactosyl residues is a pre-requisite for addition of sialic acids, a defect in B4GALT1 exerts an indirect effect to block addition of sialic acid residues and, therefore, may alter the half-life of plasma glycoproteins. Defects in glycosylation have been reported to impair intracellular trafficking of various glycoproteins—including the LDL receptor. Further, structural abnormalities in N-linked oligosaccharides have the potential to alter protein folding, which in turn could alter the function of glycoproteins and their secretion. A large percentage of proteins contain N-linked glycosylation, including cell surface receptors (e.g., LDL receptors and insulin receptors) as well as various circulating plasma proteins (e.g., apolipoprotein B and fibrinogen). There have been reports of patients with genetic disease due to homozygosity for protein-truncating mutations in the B4GALT1 gene. One such patient had a severe phenotype characterized by a) severe neurodevelopmental abnormalities (including hydrocephalus), b) myopathy, and c) blood clotting abnormalities. As predicted, oligosaccharides derived from circulating transferrin lacked galactose and sialic acid residues. Two additional patients with the same genetic defect presented with a milder phenotype, characterized by coagulation disturbances, hepatopathy, and dysmorphic features.
Cardiovascular disease is the leading cause of death in the United States and other westernized countries. Major risk factors for atherothrombotic cardiovascular diseases such as stroke and myocardial infarction include increased blood cholesterol and thrombotic tendency. Many proteins that are involved in lipid metabolism and coagulation are glycosylated and, thus, subject to modulation by B4GALT1. Knowledge of genetic factors underlying the development and progression of cardiovascular conditions could improve risk stratification and provide the foundation for novel therapeutic strategies.